Arylalkane-sulfonamides having endothelin-antagonist activity

Abstract

The invention relates to novel aryl-alkane-sulfonamides and their use as active ingredients in the preparation of pharmaceutical compositions. The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more of those compounds and especially their use as endothelin receptor antagonists.

1. A compound of the formula I 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  and R 2  represent aryl or heteroaryl; 
 R 3  represents phenyl; mono-, di- or tri-substituted phenyl substituted with substituents selected from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, phenyl, lower alkoxy, amino, lower alkylamino, amino-lower alkyl, trifluoromethyl, trifluoromethoxy, halogen, lower alkylthio, hydroxy, hydroxy-lower alkyl, cyano, carboxyl, lower alkanoyl and formyl; benzofuranyl; or heteroaryl; 
 R 4  represents hydrogen; halogen; trifluoromethyl; lower alkyl; lower alkyl-amino; lower alkoxy; lower alkyl-sulfono; lower alkyl-sulfinyl; lower alkylthio; lower alkylthio-lower alkyl; hydroxy-lower alkyl; lower alkyl-oxy-lower alkyl; hydroxy-lower alkyl-oxy-lower alkyl; hydroxy-lower alkyl-amino; lower alkyl-amino-lower alkyl; amino; di-lower alkyl-amino; [N-(hydroxy-lower alkyl)-N-(lower alkyl)]-amino; aryl; aryl-amino; aryl-lower alkyl-amino; aryl-thio; aryl-lower alkyl-thio; aryloxy; aryl-lower alkyl-oxy; aryl-lower alkyl; aryl-sulfinyl; heteroaryl; heteroaryl-oxy; heteroaryl- lower alkyl-oxy; heteroaryl-amino; heteroaryl-lower alkyl-amino; heteroaryl-thio; heteroaryl-lower alkyl-thio; heteroaryl-lower alkyl; heteroaryl-sulfinyl; heterocyclyl; heterocyclyl-lower alkyl-oxy; heterocyclyl-oxy; heterocyclyl-amino; heterocyclyl-lower alkyl-amino; heterocyclyl-thio; heterocyclyl-lower alkyl-thio; heterocyclyl-lower alkyl; heterocyclyl-sulfinyl; cycloalkyl; cycloalkyl-oxy; cycloalkyl-lower alkyl-oxy; cycloalkyl-amino; cycloalkyl-lower alkyl-amino; cycloalkyl-thio; cycloalkyl-lower alkyl-thio; cycloalkyl-lower alkyl; or cycloalkyl-sulfinyl; 
 X represents oxygen; sulfur; NH; CH 2  or a bond; 
 Y represents oxygen; sulfur or —NH—; 
 Z represents oxygen; sulfur, —NH— or a bond; 
 Q represents —(CH 2 ) k —; —(CH 2 ) m —C≡C—(CH 2 ) p —, in case p represents 0 (zero), Z represents a bond; or —CH 2 -cyclopropylen-CH 2 —; 
 k represents the numbers 2, 3, 4, 5, or 6; 
 m represents the numbers 1, 2, or 3; 
 p represents the numbers 0, 1, 2 or 3; 
 n represents the numbers 1, 2, or 3; 
 or pure diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates, the meso-forms or pharmaceutically acceptable salts thereof. 
 
     
     
       2. The compound of  claim 1 , wherein R 1 , R 2 , R 4 , Q, Y, Z and n are as defined in  claim 1 , X, represents oxygen and R 3  represents phenyl or mono-substituted phenyl substituted with halogen, lower alkyl, lower alkenyl, lower alkoxy, amino, lower alkyl-amino, lower alkyl-thio, hydroxy, hydroxymethyl or lower alkanoyl;
 or pharmaceutically acceptable salts thereof. 
 
     
     
       3. The compound of  claim 1 , wherein R 1 , R 2 , R 4 , Q, and n are as defined in  claim 1 , X, Y and Z represent oxygen and R 3  represents phenyl or mono-substituted phenyl substituted with halogen, lower alkyl, lower alkenyl, lower alkoxy, amino, lower alkyl-amino, lower alkyl-thio, hydroxy, hydroxymethyl or lower alkanoyl;
 or pharmaceutically acceptable salts thereof. 
 
     
     
       4. The compound of  claim 1 , wherein R 1 , R 2 , R 4 , and n are as defined in  claim 1 , X, Y and Z represent oxygen, Q represents —(CH 2 ) k — with k=2 or 3 and R 3  represents phenyl or mono-substituted phenyl substituted with halogen, lower alkyl, lower alkenyl, lower alkoxy, amino, lower alkyl-amino, lower alkyl-thio, hydroxy, hydroxymethyl or lower alkanoyl;
 or pharmaceutically acceptable salts thereof. 
 
     
     
       5. The compound of  claim 1 , wherein R 1 , R 4 , and n are as defined in  claim 1 , X, Y and Z represent oxygen, Q represents —(CH 2 ) k — with k=2 or 3, R 2  represents heteroaryl and R 3  represents phenyl or mono-substituted phenyl substituted with halogen, lower alkyl, lower alkenyl, lower alkoxy, amino, lower alkyl-amino, lower alkyl-thio, hydroxy, hydroxymethyl or lower alkanoyl;
 or pharmaceutically acceptable salts thereof. 
 
     
     
       6. The compound of  claim 1 , wherein
 R 1 , R 4 , and n are as defined in  claim 1 , X, Y and Z represent oxygen, Q represents —(CH 2 ) 2 —, R 2  represents heteroaryl, R 3  represents phenyl or mono-substituted phenyl substituted with halogen, lower alkyl, lower alkenyl, methoxy, amino, lower alkyl-amino, lower alkyl-thio, hydroxy, hydroxymethyl or lower alkanoyl; 
 or pharmaceutically acceptable salts thereof. 
 
     
     
       7. A compound of formula II 
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 3 , R 4 , Y, Q, Z and n are as defined in  claim 1  above, or pharmaceutically acceptable salts thereof. 
       
     
     
       8. A compound of formula III 
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 4 , Y, Q, Z and n are as defined in  claim 1  above, or pharmaceutically acceptable salts thereof. 
       
     
     
       9. A compound of formula IV 
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 4 , Q and n are as defined in  claim 1  above, or pharmaceutically acceptable salts thereof. 
       
     
     
       10. A compound of formula V 
       
         
           
           
               
               
           
         
         wherein R 1 , R 2  and n are as defined in  claim 1  above, or pharmaceutically acceptable salts thereof. 
       
     
     
       11. The compound of  claim 10 , wherein R 2  in formula V represents heteroaryl or pharmaceutically acceptable salts thereof. 
     
     
       12. The compound of  claim 1  wherein said compound is selected from the group consisting of:
 2-Phenyl-ethanesulfonic acid {6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-p-tolyl -pyrimidin-4-yl}-amide, 
 2-Phenyl-ethanesulfonic acid {6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-p-tolyl-[2,2′]bipyrimidinyl-4-yl}-amide, 
 2-Phenyl-ethanesulfonic acid {5-(2-methoxy-phenoxy)-6-[2-(pyrimidin-2-yloxy)-ethoxy]-[2,2′]bipyrimidinyl-4-yl}-amide, 
 2-Phenyl-ethanesulfonic acid {5-(2-methoxy-phenoxy)-6-[2-(5-methoxy-pyrimidin -2-yloxy)-ethoxy]-[2,2′]bipyrimidinyl-4-yl}-amide, 
 2-Thiophen-2-yl-ethanesulfonic acid [6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-(4-chloro-phenyl)-pyrimidin-4-yl]-amide, 
 2-Thiophen-2-yl-ethanesulfonic acid {5-(4-chloro-phenyl)-6-[2-(5-methoxy-pyrimidin -2-yloxy)-ethoxy]-pyrimidin-4-yl}-amide, 
 2-Pyridin-2-yl-ethanesulfonic acid [6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide, and pharmaceutically acceptable salts thereof. 
 
     
     
       13. A pharmaceutical composition comprising one or more of the compounds of any one of  claims 1 ,  7 ,  8 ,  9  and  10  and a pharmaceutically acceptable carrier. 
     
     
       14. A process for preparing a pharmaceutical composition, comprising mixing one or more compounds of any one of  claims 1 ,  7 ,  8 ,  9  and  10  with a pharmaceutically acceptable carrier.